Virus World

An experiment tests whether the gene-editing technology can stop the virus from replicating, which would ultimately wipe out the infection. 

IN JULY, AN HIV-positive man became the first volunteer in a clinical trial aimed at using Crispr gene editing to snip the AIDS-causing virus out of his cells. For an hour, he was hooked up to an IV bag that pumped the experimental treatment directly into his bloodstream. The one-time infusion is designed to carry the gene-editing tools to the man’s infected cells to clear the virus. Later this month, the volunteer will stop taking the antiretroviral drugs he’s been on to keep the virus at undetectable levels. Then, investigators will wait 12 weeks to see if the virus rebounds. If not, they’ll consider the experiment a success. “What we’re trying to do is return the cell to a near-normal state,” says Daniel Dornbusch, CEO of Excision BioTherapeutics, the San Francisco-based biotech company that’s running the trial. HIV attacks immune cells in the body called CD4 cells and hijacks their machinery to make copies of itself. But some HIV-infected cells can go dormant—sometimes for years—and not actively produce new virus copies. These so-called reservoirs are a major barrier to curing HIV. “HIV is a tough foe to fight because it’s able to insert itself into our own DNA, and it’s also able to become silent and reactivate at different points in a person’s life,” says Jonathan Li, a physician at Brigham and Women’s Hospital and HIV researcher at Harvard University who’s not involved with the Crispr trial. Figuring out how to target these reservoirs—and doing it without harming vital CD4 cells—has proven challenging, Li says. While antiretroviral drugs can halt viral replication and clear the virus from the blood, they can’t reach these reservoirs, so people have to take medication every day for the rest of their lives. But Excision BioTherapeutics is hoping that Crispr will remove HIV for good.

Crispr is being used in several other studies to treat a handful of conditions that arise from genetic mutations. In those cases, scientists are using Crispr to edit peoples’ own cells. But for the HIV trial, Excision researchers are turning the gene-editing tool against the virus. The Crispr infusion contains gene-editing molecules that target two regions in the HIV genome important for viral replication. The virus can only reproduce if it’s fully intact, so Crispr disrupts that process by cutting out chunks of the genome. In 2019, researchers at Temple University and the University of Nebraska found that using Crispr to delete those regions eliminated HIV from the genomes of rats and mice. A year later, the Temple group also showed that the approach safely removed viral DNA from macaques with SIV, the monkey version of HIV. That was an important step toward testing the treatment in people, says Kamel Khalili, a professor of microbiology at Temple University who led the work and is a cofounder of Excision Biotherapeutics. “You don’t want to eliminate the viral genome but at the same time cause any disruption in another part of the human genome and then create another set of problems for the patients,” he says. “We had to make sure that we identified a region within HIV that did not overlap with the human genome.”  Dornbusch thinks this strategy will spare patients from serious side effects and “off-target” edits—unintentional cuts elsewhere in the genome that could cause problems such as cancer. The regions targeted by the company’s Crispr therapy are also in a part of the genome that tends to stay the same even when HIV evolves. That’s important because the virus mutates rapidly, and the researchers don’t want a moving target. This isn’t the first time scientists have tried to use gene editing in the hope of curing people with HIV, but other efforts have focused on a protective mutation in a gene called CCR5. In the 1990s, scientists found that people with this naturally occurring mutation didn’t get HIV when exposed to it. The mutation—known as delta 32—thwarts the virus’s ability to get inside immune cells. In 2009, California-based Sangamo Therapeutics used an older editing technology called zinc finger nucleases to add that protective mutation into patients’ T cells—an important part of the immune system. Those trials have had limited success.

In 2017, Chinese scientists combined Crispr with a bone marrow transplant in an attempt to cure a patient with HIV and leukemia. In a typical transplant, donor stem cells are transferred to a recipient to replace their cancerous blood cells. These cells go on to form new, healthy blood cells. To also address the patient’s HIV, researchers edited the donor stem cells with Crispr to disable CCR5. But after the transplant, only a small percentage of the patient’s bone marrow cells ended up with the desired edit. Then in 2018, Chinese scientist He Jiankui used Crispr to edit the CCR5 mutation into the genomes of twin baby girls to make them resistant to HIV. Fraught with ethical violations, the experiment was widely condemned by scientists. He’s research was suspended by the Chinese government, and he served a three-year prison sentence. While the twins were born healthy, only some of their cells were successfully edited, meaning the girls might in fact not be immune to HIV. As of 2022, two people have now been cured of HIV after receiving bone marrow transplants from donors with the CCR5. Known as the Berlin patient and the London patient, both had cancer and received transplants to treat their disease. But these transplants aren’t a viable option for most people—they’re highly risky, and donors with the delta 32 mutation are scarce. But a third person was declared cured of HIV earlier this year after she received a new type of transplant involving umbilical cord blood.

The Excision trial will eventually enroll nine participants and test three dosage amounts to determine which is most effective. Investigators will measure each person’s viral load and CD4 count before receiving the therapy and after they stop taking antiretroviral drugs. The ultimate goal is to get viral loads down to an undetectable level—that is, less than 200 copies of HIV per milliliter of blood. At this level, HIV can’t be passed on through sex. The challenge for Excision will be getting Crispr to enough cells to bring HIV down to undetectable levels. The company is using an engineered virus to shuttle the gene-editing components to patients’ HIV-infected CD4 cells. But so far, there’s little human data on how well Crispr works when it’s delivered directly to the body. “It’s possible that you get the virus to such low levels that if a person’s immune system were intact, they might be able to keep the virus at bay such that they don’t have to take antiretroviral therapy anymore,” says Rowena Johnston, vice president and director of research for amfAR, the Foundation for AIDS Research.

And even though these drugs are very effective, Johnston says, many people would rather be completely free of the virus. A single Crispr infusion—if it works—would eliminate the need for daily pills. “People with HIV still live with a lot of stigma and internalized shame,” she says. “I think a cure is something that addresses that much better than lifelong therapy, regardless of how easy that therapy becomes.”

Before its discovery in New York’s wastewater, the virus made a series of ominous appearances around the world.  At the beginning of this year, there was a thrum of excitement among global health experts: Eradication of polio, a centuries-old foe that has paralyzed legions of children around the globe, seemed tantalizingly close. Pakistan, one of only two countries where wild poliovirus still circulates, had not recorded cases in more than a year. Afghanistan had reported only four. But eradication is an uncompromising goal. The virus must disappear from every part of the world and stay gone, regardless of wars, political disinterest, funding gaps or conspiracy theories. New signs of the virus in a single country can derail the effort.  In polio’s case, there were several ominous setbacks. Malawi in February announced its first case in 30 years, a 3-year-old girl who became paralyzed following infection with a virus that appeared to be from Pakistan. Pakistan itself went on to report 14 cases, eight of them in a single month this spring. In March, Israel reported its first case since 1988. Then, in June, British authorities declared an “incident of national concern” when they discovered the virus in sewage. By the time New York City detected the virus in wastewater last week, polio eradication seemed as elusive as ever. “It’s a poignant and stark reminder that polio-free countries are not really polio-risk free,” said Dr. Ananda Bandyopadhyay, deputy director for polio at the Bill & Melinda Gates Foundation, the largest supporter of polio eradication efforts.  The virus is always “a plane ride away,” he added. Polio is a highly contagious and sometimes deadly enemy, capable of ravaging the nervous system and causing paralysis within hours. Those who recover could relapse and become seriously ill years later.

The virus multiplies in the intestine for weeks and could spread through feces or contaminated food or water — for example, when an infected child uses the toilet, neglects washing hands and then touches food.  For decades the virus terrorized families, causing paralysis among more than 15,000 American children each year and hundreds of thousands more worldwide. Its retreat is a triumph of vaccination. After the first vaccine arrived in 1955, the number of cases dropped precipitously, and by 1979 the United States was declared polio-free. Although the United States and Britain have high immunization rates, they also have pockets of low immunity that allow the virus to flourish. In those communities, all unvaccinated people — not just children — are at risk. If polio continues to spread in the United States for a year, the country may lose its polio-free status under W.H.O. guidelines. The Covid-19 pandemic left many other countries vulnerable to a resurgence of polio: It disrupted vaccination drives for months and diverted staff and resources away from prevention programs, resulting in the worst backslide in immunization rates in 30 years. “The moment you take your eye off the ball, you know that the virus will simply reappear,” said Aidan O’Leary, director for polio eradication at the World Health Organization. “We have to literally face down every single chain of transmission that we can identify.”  Aid organizations first aspired to eradicate polio in 1988 and poured billions of dollars into the Global Polio Eradication Initiative, a consortium of six partners, including the Gates Foundation, the W.H.O. and the Centers for Disease Control and Prevention. Despite the recent cases, the progress is unmistakable: Global cases of polio have fallen by 99 percent — from 350,000 cases of paralysis in 1988 to about 240 so far this year.

After a 32-year campaign to rid the African continent of wild poliovirus, the World Health Organization declared Africa entirely polio-free. Nobody will ever know the identity of the thousands of African children who were not killed or paralyzed by polio this year. They would have been hard to keep track of no matter what because in ordinary times, they would have followed thousands last year and thousands the year before and on back in a generations-long trail of suffering and death. Instead, no African children were claimed by polio this year or last year or the year before. It was in 2016 that the last case of wild, circulating polio was reported in Nigeria—the final country on the 54-nation African continent where the disease was endemic. And with a required multi-year waiting period now having passed with no more cases, the World Health Organization today officially declared the entirety of Africa polio-free. A disease that as recently as the late 1980s was endemic in 125 countries, claiming 350,000 children per year, has now been run to ground in just two remaining places, Pakistan and Afghanistan, where there have been a collective 102 cases so far in 2020. That’s 102 too many, but there is no denying the scope of the WHO announcement. “Today’s victory over the wild poliovirus in the African region is a testament to what can happen when partners from a variety of sectors join forces to accomplish a major global health goal,” says John Hewko, general secretary and CEO of Rotary International. “[It is] something the world can and should aspire to during these turbulent times.”

It was Rotary, an international nonprofit service organization, that kicked off the polio endgame in 1988 with the launch of the Global Polio Eradication Initiative (GPEI). That program aimed to leverage the power of Rotary’s 35,000 clubs and 1.22 million members in 200 countries and territories worldwide to make polio only the second human disease—after smallpox—to be pushed over the brink of extinction. The job was made easier by the partners Rotary immediately attracted: the WHO, the U.S. Centers for Disease Control and Prevention (CDC) and UNICEF. The Bill and Melinda Gates Foundation joined in 2007, followed by Gavi, the Vaccine Alliance, just last year. The 32-year initiative has depended on volunteer workers and charitable donations, which together have produced an army of 20 million field workers administering vaccines to over 2.5 billion children at a cost of $17 billion. Some countries were a lighter lift than others. In the U.S. the disease was eradicated in 1979, well before the GPEI even began its work. Other nations followed: In 1994 the Americas were declared polio-free. Europe as a whole got a clean bill of health in 2002, when all 53 countries in the WHO’s designated European region were declared free of the virus. Massive vaccination efforts began in India in 1997, which eradicated the virus in 2014. 

How Polio Was Eradicated from the African Continent

But Africa, with its vast sprawl of village populations, long distances to urban hospitals, spotty infrastructure like adequate roads and reliable “cold chains”—refrigerated transport networks to keep vaccines viable—was always going to present special challenges. In 1996, when the case count on the continent regularly reached 75,000 victims every year, South African President Nelson Mandela partnered with Rotary to launch the “Kick Polio Out of Africa” Campaign, and the group scrambled fast—or as fast as was possible with so many children to vaccinate on so vast a land mass. In 2000, the first synchronized campaigns began in 17 countries, with 76 million children being vaccinated by tens of thousands of volunteers. The work fanned out across the continent from there, including an especially heavy push from 2008 to 2010, when an outbreak in 24 countries in western and central Africa was met by a large-scale, multi-national vaccination of 85 million children. Finally, Nigeria stood alone as the only African nation where the disease was still endemic, in part because of resistance by religious leaders in the northern part of the country who objected western interference in local affairs and claimed that the vaccine was unsafe. That opposition broke down, partly thanks to Muhammad Sanusi II, the Emir of the city of Kano—a hereditary leader descended from a ruling family—who appeared at a public ceremony before the kick off of a seasonal vaccination campaign in 2016, called for a vial of polio vaccine to be brought to the stage, and with the audience watching, broke its seal and drank down its entire contents. That year, the country recorded its last case of polio, and this year, Nigeria’s WHO certification is the reward for its efforts....

In New Zealand, rapid, science-based risk assessment linked to early, decisive government action was critical to containing Covid-19. Soon after initial descriptions of an outbreak in Wuhan, China, were shared, reports in late January 2020 (https://www.thelancet.com/journals/lancet/ article/PIIS0140-6736(20)30260-9/fulltext) confirmed that Covid-19 was almost certain to become a serious pandemic. Despite New Zealand’s geographic isolation, we knew that introduction of SARS-CoV-2 was imminent because of the large numbers of tourists and students who arrive in the country each summer, predominantly from Europe and mainland China. Our disease models indicated that we could expect the pandemic to spread widely, overwhelm our health care system, and disproportionately burden indigenous Maori and Pacific peoples. New Zealand began implementing its pandemic influenza plan in earnest in February, which included preparing hospitals for an influx of patients. We also began instituting border-control policies to delay the pandemic’s arrival.

New Zealand’s first Covid-19 case was diagnosed on February 26 (see Figure 1). That same week, the WHO–China Joint Mission’s report on Covid-19 (www.who.int/docs/default-source/ coronaviruse/who-china-joint-mission-on-covid-19 -final-report.pdf) showed that SARS-CoV-2 was behaving more like severe acute respiratory syndrome (SARS) than like influenza, which suggested that containment was possible....

Published in NEJM (August 7, 2020):

https://doi.org/10.1056/NEJMc2025203

NEW YORK (AP) — Some U.S. health officials are conceding that monkeypox is probably not going away anytime soon. The disease’s spread is slowing but the virus is so widespread that elimination is unlikely, the Centers for Disease Control and Prevention said.  That conclusion was in a recent CDC report, and echoed Friday by Marc Lipsitch, director of science in the agency’s disease-forecasting center. Lipsitch hesitated to say monkeypox is permanently here to stay, but he said it stands to be a continuing threat for the next few years. “It’s in many geographic locations within the country” as well as in other countries, Lipsitch told The Associated Press. “There’s no clear path in our mind to complete elimination domestically.” The virus has mainly spread among gay and bisexual men, though health officials continue to stress that anyone can be infected. It’s important that people at risk take steps to prevent spread and that vaccination efforts continue, Lipsitch said. The CDC report contained some good news: The U.S. outbreak seems to have peaked in early August. The average number of daily cases being reported — fewer than 150 — is about a third what it was reported in the middle of the summer, and officials expect the decline will continue for at least the next several weeks.  Lipsitch attributed the good news to increasing vaccinations, cautious behavior by people at risk and infection-derived immunity in the highest risk populations. Dr. Tom Inglesby, director of the Johns Hopkins Center for Health Security, agreed that it’s unlikely that spread of monkeypox will stop in the U.S. anytime soon, but he said it’s still possible in the long term.

If domestic transmission were stopped, infections may still continue if people catch the virus while traveling internationally, he said. But the declining cases makes it seem like “we’ve turned a real corner.” “The efforts underway are succeeding, and should be continued, if not intensified,” he said. With case numbers going down, this is a good time for local health departments to take a new stab at doing intensive contact tracing to try to stop chains of transmission, he said. Monkeypox is endemic in parts of Africa, where people have been infected through bites from rodents or small animals, but it wasn’t considered a disease that spreads easily among people until May, when infections emerged in Europe and the U.S.  There have been more than 67,000 cases reported in countries that have not historically seen monkeypox. The U.S. has the most infections of any country — more than 25,600. One U.S. death has been attributed to monkeypox. More than 97% of U.S. cases are men. The vast majority have been men who reported recent sexual contact with other men. Though cases have been declining, the proportion of new cases that have information about recent sexual contact is also down, officials said. That’s causing a growing blind spot about how the virus may be spreading, Lipsitch noted.

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The Associated Press Health & Science Department receives support from the Howard Hughes Medical Institute’s Department of Science Education. The AP is solely responsible for all content.

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CDC Report (Sept. 23, revised Sept. 29, 2022) available at:

https://www.cdc.gov/poxvirus/monkeypox/cases-data/technical-report/report-3.html 

An antisense drug developed by GlaxoSmithKline has been shown to suppress the hepatitis B virus (HBV) in a  phase 2 trial, raising hopes of a “functional cure” for the widespread disease. HBV affects an estimated 260 million people worldwide, according to GSK. While drugs to treat it are available – such as Gilead’s polymerase inhibitor Viread (tenofovir) – there is still no curative treatment, and the company hopes that GSK3228836 could fill that void. Most people are able to shake off HBV infection in time, but in a majority of children and a minority of adults, HBV infection can become chronic and lead to cirrhosis as well as liver cancer, whilst also allowing transmission of the virus to others. Chronic HBV kills around 900,000 people every year. In the phase 2a trial, GSK3228836 was able to reduce two biomarkers of chronic HBV infection – hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA – compared to placebo after four weeks treatment. The trial involved four patients previously treated with antivirals and 12 who were new to drug therapy for HBV, and across both groups there were six patients who had a 3-log (99.9%) or greater reduction in HBsAg levels after 29 days. 

In four of the big responders, levels of the biomarker fell below the limit of detection, and in one case that persisted for six months. Meanwhile, five of 12 previously-untreated patients had 2-log (90%) or a greater reduction in HBV DNA. The results are still preliminary but according to GSK show clear signs of a therapeutic effect that will be tested in a phase 2b programme, due to start before the end of the year. The company’s senior vice president for development, Christopher Corsico, said that the results are “a potential step forward toward the goal of assessing sustained functional cure for people with chronic hepatitis B.” The company’s senior vice president for development, Christopher Corsico, said that the results are “a potential step forward toward the goal of assessing sustained functional cure for people with chronic hepatitis B.” Experts talk about a functional cure in HBV – defined as the complete loss of HBsAg – because it is impossible to tell biologically if the virus has been eliminated from the body. That is because viral DNA fragments can lurk in cells, hiding from current drug therapy and evading the immune system. GSK3228836 is designed to target viral DNA directly, which could give it a chance of targeting all traces of the virus in the body, and prevent it from becoming a chronic infection. GSK licensed the drug from longstanding partner Ionis as part of a two-drug deal last year, paying $25 million upfront with milestone payments taking the value of the deal up to $262 million.

If either of the antisense drugs covered by that license make it through to market, that would look like a very good deal, particularly given the sheer scale of HBV infection worldwide. The first drugs that were able to effect a cure for chronic hepatitis C virus (HCV), such as Gilead’s Harvoni (sofosbuvir/ledipasvir), quickly amassed blockbuster revenues, although that tailed off quickly as the pool of available patents declined. Analysts at William Blair have suggested that the market for an HBV cure could be around the same size as HCV, which peaked at around $10 billion a year. There’s competition coming through the industry pipeline though. Last year, Roche paid a whopping $200 million upfront to license an RNA interference drug for HBV from Dicerna called DCR-HBVs (now RG6346), with another $1.47 billion in potential milestones. The drug is in phase 1/2 development. Meanwhile, Johnson & Johnson paid $175 million upfront for Arrowhead Pharma’s RNAi candidate ARO-HBV (now JNJ-3989) which is also in a phase 2 trial.

No matter what happens now, the virus will continue to circulate around the world.  The coronavirus that causes COVID-19 has sickened more than 16.5 million people across six continents. It is raging in countries that never contained the virus. It is resurgingin manyof the ones that did. If there was ever a time when this coronavirus could be contained, it has probably passed. One outcome is now looking almost certain: This virus is never going away.  The coronavirus is simply too widespread and too transmissible. The most likely scenario, experts say, is that the pandemic ends at some point—because enough people have been either infected or vaccinated—but the virus continues to circulate in lower levels around the globe. Cases will wax and wane over time. Outbreaks will pop up here and there. Even when a much-anticipated vaccine arrives, it is likely to only suppress but never completely eradicate the virus. (For context, consider that vaccines exist for more than a dozen human viruses but only one, smallpox, has ever been eradicated from the planet, and that took 15 years of immense global coordination.) We will probably be living with this virus for the rest of our lives. Back in the winter, public-health officials were more hopeful about SARS-CoV-2, the coronavirus that causes COVID-19. SARS, a closely related coronavirus, emerged in late 2002 and infected more than 8,000 people but was snuffed out through intense isolation, contact tracing, and quarantine. The virus was gone from humans by 2004. SARS and SARS-CoV-2 differ in a crucial way, though: The new virus spreads more easily—and in many cases asymptomatically. The strategies that succeeded with SARS are less effective when some of the people who transmit COVID-19 don’t even know they are infected. “It’s very unlikely we’re going to be able to declare the kind of victory we did over SARS,” says Stephen Morse, an epidemiologist at Columbia University.

If not, then what does the future of COVID-19 look like? That will depend, says Yonatan Grad, on the strength and duration of immunity against the virus. Grad, an infectious-disease researcher at Harvard, and his colleagues have modeled a few possible trajectories. If immunity lasts only a few months, there could be a big pandemic followed by smaller outbreaks every year. If immunity lasts closer to two years, COVID-19 could peak every other year.  At this point, how long immunity to COVID-19 will last is unclear; the virus simply hasn’t been infecting humans long enough for us to know. But related coronaviruses are reasonable points of comparison: In SARS, antibodies—which are one component of immunity—wane after two years. Antibodies to a handful of other coronaviruses that cause common colds fade in just a year. “The faster protection goes away, the more difficult for any project to try to move toward eradication,” Grad told me. This has implications for a vaccine, too. Rather than a onetime deal, a COVID-19 vaccine, when it arrives, could require booster shots to maintain immunity over time. You might get it every year or every other year, much like a flu shot. Even if the virus were somehow eliminated from the human population, it could keep circulating in animals—and spread to humans again. SARS-CoV-2 likely originated as a bat virus, with a still-unidentified animal perhaps serving as an intermediate host, which could continue to be a reservoir for the virus. (SARS also originated in bats, with catlike palm civets serving as an intermediate host—which led officials to order the culling of thousands of civets.) Timothy Sheahan, a virologist at the University of North Carolina at Chapel Hill, wonders if, with SARS-CoV-2 so widespread across the globe, humans might be infecting new species and creating new animal reservoirs. “How do you begin to know the extent of virus spread outside of the human population and in wild and domestic animals?” he says. So far, tigers at the Bronx Zoo and minks on Dutch farms seem to have caught COVID-19 from humans and, in the case of the minks, passed the virus back to humans who work on the farm...